Orofacial clefts (OFCs) are the most common craniofacial birth defect in humans and are caused by multiple genetic and environmental risk factors. Elucidating the etiology of OFCs is critical not only for our knowledge of developmental biology and for how clefts arise, but ultimately for improved prevention, treatment, and prognosis for individuals affected by orofacial clefting. Genetic studies of nonsyndromic OFCs have recently focused on genome-wide association studies (GWAS), but the associated regions account for only a fraction of the heritable risk of OFCs indicating that additional genetic risk factors have yet to be identified. Possible sources of this ?missing heritability? are rare coding variants, which are not a major component of commercial GWAS panels and are best identified by sequencing. There is great value in sequencing families given that causal variants that segregate in families usually have larger effect sizes than those found in families of sporadic cases. The goal of this project is to prioritize families for exome sequencing by including subclinical OFC features that we hypothesize are mild manifestations of OFCs. We have identified 72 deeply phenotyped, multiplex families that segregate OFCs and subclinical phenotypes in an apparently Mendelian manner. We hypothesize these families are more likely to carry rare coding variants of large effect and that this approach will allow us to identify novel genes for OFCs and subclinical phenotypes.